Gelatin capsule having adjusted water activity

ABSTRACT

A gelatin capsule having adjusted water activity and preserved in a closed system, which contains, packed herein, an additive(s) selected from the group consisting of carboxymethyl cellulose calcium, crosscarmellose sodium, partially gelatinized starch and polyvinyl polypyrrolidone in the proportion of 50 to 150 wt. % of the total quantity of the gelatin of the said capsule.

This application is a 371 of PCT/JP96/00728 filed Mar. 21, 1996.

TECHNICAL FIELD

The present invention relates to a gelatin capsule having an improvedinternal moisture stability in a closed system through the adjustment ofthe water activity of the content in the capsule.

BACKGROUND ART

Quality of a capsule, that is, stability of its structure,pharmacological activity of drugs as the content, and appearance thereofis closely related to the water or moisture activity. For example, ithas been known that, even if a gelatin capsule was manufactured under anappropriate condition, the moisture in the capsule coating and thecontent drugs evaporates during preservation in a closed system,especially under heating, which possibly leads to hyper humiditycondition (hyper water activity) of inside of the capsule. When acontent drug comprises an active ingredient liable to change withmoisture, or when moisture cannot be separated easily from an activeingredient and impurities unstable to moisture are co-exist, the contentdrug necessarily contacts with free water present inside of a capsuleand can be un-stabilized with the elapse of time. This would result innot only the change in the appearance such as coloration but also thedecrease in the activity of an active ingredient. In addition, thegelatin capsule itself may become insoluble and soft, which may befollowed by the deformation or the like. In general, the adjustment ofwater activity, especially the reduction thereof, was carried out byplacing a drying agent such as silica gel into a container for packagingcapsules so as to reduce the internal moisture of a capsule. However, itis not easy to adjust the water content in the capsule coatingappropriately by this method. Especially, in the case of gelatincapsules, too much decrease in the water content might cause a crack ora crack break, leading to the damage or deformation of capsules. Thenormal water content or moisture content of a gelatin capsule coating isbetween 12 and 16% and, when it becomes below 10%, in particular, below7-8%, cracks may happen only by slight impact. Therefore, it isdesirable to decrease the content of free water inside of a capsulewhile maintaining the water content in the gelatin coating adequately.However, the manufacture of such capsules was difficult.

There have been reported stabilized gelatin capsules, for example, inJapanese Patent Publication (KOKAI) No. 80,930/1991, Japanese PatentPublication (KOKAI) No. 145,017/1992, Japanese Patent Publication(KOKAI) No. 159,218/1992 and the like. However, they all relate togelatin capsules which contain a stabilizer in the gelatin coating anddo not mention at all about the adjustment of water activity inside ofcapsules. Therefore, these literatures do not solve the problems above.Japanese Patent Publication (KOKAI) No. 24,014/1978 reported gelatincapsules containing polyvinyl pyrrolidone. However, the amount ofpolyvinyl pyrrolidone used per capsule is only a little and the purposeof the use thereof is the adjustment of the release rate of a drug.

Under the conditions above, the present inventors have studiedintensively to establish a method for adjusting the water activityinside of a capsule (i.e., internal water activity of a capsule)appropriately, and to develop a capsule having adjusted water activity.

As a result, the present invention has been established on the basis ofthe finding that it is useful to add a certain substance which serves asa water activity regulating agent to the capsule content in order toadjust the internal water activity of a capsule appropriately withoutaffecting adversely the gelatin coating.

DISCLOSURE OF THE INVENTION

The present invention provides a gelatin capsule having adjusted wateractivity and preserved in a closed system, which contains, packedherein, an additive(s) selected from the group consisting ofcarboxymethyl cellulose calcium, crosscarmellose sodium, partiallygelatinized starch and polyvinyl polypyrrolidone in the proportion of 50to 150 wt. % of the total quantity of the gelatin of the said capsule.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing the relation between the temperature and thewater activity of gelatin which is preserved in a closed system.

FIG. 2 is a graph showing the stability of aspirin in a capsule whichcontains aspirin alone or in association with an additive (CS(cornstarch); MCC (crystalline cellulose); CMS (carboxymethyl celluloseCa); PCS (partially gelatinized starch)), when it was preserved in aclosed system while heating at 60° C.

FIG. 3 is a graph showing the relation between the adding ratio of anadditive to gelatin and to gelatin the water activity of gelatin beadsin a mixture which contains gelatin beads and an additive (PVPP(polyvinyl polypyrrolidone); Ac-di-Sol; CMC-Ca; PCS) in various mixingratios and was preserved in a closed system (25° C.).

FIG. 4 is a graph showing the relation between the adding ratio of anadditive to gelatin and the water activity of gelatin beads in a mixturesimilar to that used in FIG. 3, which was preserved in a closed systemwhile heating (45° C.).

FIG. 5 is a graph showing the relation between the adding ratio of anadditive to gelatin and the water activity of gelatin beads in a mixturesimilar to that used in FIG. 3, which was preserved in a closed systemwhile heating (60° C.).

PREFERRED EMBODIMENT TO CARRY OUT THE INVENTION

The coating of the gelatin capsules of the present invention preferablycontains as a principal component gelatin and optionally a small amountof an additive(s) for capsule coating generally used in the field ofpharmaceutical industries, for example, polyethylene glycol and thelike.

For purposes of the present invention, an selected additive serves as awater activity regulating agent (or a regulator) as mentioned above ispacked in a capsule in the proportion of about 50 to 150 wt. %,preferably about 50 to 120 wt. %, more preferably about 50 to 100 wt. %,further more preferably about 70 to 100 wt. %, especially preferablyabout 75 to 90 wt. % of the total quantity of the gelatin coating.

If the amount of an additive(s) is too little, the internal wateractivity cannot be controlled effectively when a capsule is preservedunder high temperature and high humidity, or for a long time, whichpossibly leads to the unstabilization or discoloration of the capsule orits content. If the amount of an additive(s) is too large, the internalwater activity could be greatly decreased under a mild condition of atroom temperature and a crack may happen on a gelatin capsule.

Throughout the specification, the term "water activity (A_(W))" means aratio of water vapor pressure (P) in a certain measurement system andthat (Po) of pure water under the same temperature and pressure as thoseof the said measurement system, and is defined by the formula:

    A.sub.W =(P/Po)×100(%).

The water activity of each of gelatin, additive(s) and the whole capsulecan be measured with any one of commercially available measuring device(e.g., Water activity (A_(W)) measurement system of DT type,manufactured by Rotronic, Inc. (Gunze Industrial Co., Ltd.)).

The total water activity of a capsule (A_(WT)) is in principle the sameas the mean water activity (A_(W)) which can be calculated from thewater activity of each of the gelatin as a component of capsule coatingand the additive(s) packed in the capsule in accordance with thefollowing formula. However, they differ from each other in such a casewhere a shift of moisture between coating and additives occurs due tothe packing of an additive(s) into a capsule.

    A.sub.W =[A.sub.W ·M(gelatin)+A.sub.W ·M(additive)]/[M(gelatin)+M(additive)]

A_(W) : mean water activity

A_(W) : individual water activity

M: individual water content

Throughout the specification, when "a change in water activity" isdiscussed in relation to the moisture stability of capsules, thedifference between the mean water activity (A_(W)) calculatedaccording-to the formula on the basis of the individual water activitybefore packing an additive(s) and the A_(WT) value of a capsulecalculated after packing the additive(s) is more important than thechange in the absolute water activity measured for each of the gelatinand the additive(s). That is, the greater the reduction of A_(WT) fromA_(W) of a capsule, the more the water transferred from the capsulecoating to an additive(s), which means that the elevation of wateractivity inside of the said capsule is under suppression. The capsulesof the present invention may contain any of pharmacologically active andpharmaceutically acceptable drugs, as long as it does not interact withadditives adversely. However, a substance which is liable to change inpharmacological activity and physicochemical characteristics such ascolor, particle size and the like due to the change in water activity,especially elevation thereof, is suited. Examples of such substancesinclude antibiotics, e.g.,7β-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamide]-(1,2,3-triazol-4-ylthimetylthio)-1-carba-3-cephem-4-carboxylicacid, and aspirin. Incidently, in some cases, such physicochemicalchange of a drug is attributable not only to the active substance butalso the contaminants accompanying to the active substance.

The gelatin capsules obtained according to the present method areunexpectedly stable when preserved in a closed system, where the gelatincapsules are usually instable. Especially, a content drug(s) whichotherwise is adversely affected by high water activity can be keptstably in a gelatin capsule even in a closed system at elevatedtemperature. At the same time, the gelatin capsule coating itself hasalso been stabilized. Accordingly, the present invention can contributeto the maintenance of the quality of capsules which have been consideredto be subject to quality deterioration during the transportation orpreservation.

Throughout the specification, the term "closed system" means a systemwhere the distribution of outside air is blocked as completely aspossible and is preferably constructed by packaging with a press-throughpackage (PTP), alumi-pillow or the like.

The capsules of the present invention can be prepared in a conventionalmanner using conventional carriers, excipients and the like, except thatan appropriate amount of additive(s) which serves as a water activityregulator is included. However, since an experiment revealed thatadditives such as cornstarch, crystalline cellulose, lactose, mannitol,sucrose and the like, which are commonly formulated into standardcapsules, affect adversely on the water activity reduction (see, TestExample 2 below), it is preferable to adjust the content of theseadditives adequately when they are used in the preparation of capsulesof the present invention. For example, a relatively slight amount ofsuch a substance, e.g., lactose, is usable as an excipient whenpreparing the capsules of the present invention on condition that itdoes not affect adversely the reduction of water activity.

EXAMPLES

The present invention will be described in more detail in the followingExamples. However, these are merely for illustration purpose and shouldnot be construed as limiting the scope of the present invention.

In the following Examples, water content and water activity of both thecoating and the content of capsules were measured under the followingconditions.

Water activity:

Device: Water activity (A_(W)) Measuring System of DT type, manufacturedby Rotronic & Co. (Gunze industrial Co., Ltd.);

Specimen: 3 g; and

Temperature of jacket: 25±2° C.; 45±2° C.; or 60±2° C.

Water content:

Thermostat: SATAKE Vacuous Thermostat;

Temperature: 60±1° C.;

Vacuous Degree: 5 mmHg or below (phosphorus pentaoxide);

Desiccation time: 4 hours; and

Specimen: 0.5-1.0 g (container: diameter 1.7 cm, thickness of specimen:about 7 mm).

The measured values of water content were expressed by the proportion(%) of the weight loss (dry wt.) to the dry weight of a specimen.

Test Example 1

Influence of Temperature on the Water Activity of Gelatin

Water activity of gelatin to be used in the capsule coating wasevaluated in a closed system under the conditions described above. Theresults obtained using gelatin alone are shown in FIG. 1.

From the FIG. 1, it is apparent that the water activity of gelatinincreases as temperature rises, i.e., 45% at 40° C.; 55% at 50° C.; and70% at 60° C. These results indicate that, when heated under a sealedcondition, moisture evaporates from the gelatin coating of a capsule,which in turn makes the condition of inside of the capsule hyperhumidity (hyper water activity).

Test Example 2

Screening of Additives Showing Reduction of Water Activity in thePresence of Gelatin

Screening of a substance suited for the reduction of water activityinside of a gelatin capsule was conducted by preserving variousadditives alone or in a 1:1 mixture with gelatin (beads) in a closedsystem and determining the water activity and water content.Specifically, 1.5 g of an additive, or a mixture of 1.5 g of an additiveand 1.5 of gelatin beads was placed in a vial, plugged to seal, and keptfor 14 days at a constant temperature (25° C., 45° C. or 60° C.). Thewater activity and water content of the individual additive and gelatinwere then measured. Water activity of an additive preserved in thepresence of gelatin beads was measured with a device for measuring thewater activity adjusted at the same temperature as storage. The watercontent of each additive following the preservation was measured underthe conditions above after removing gelatin beads from a mixture. Theresults are shown in Table 1 below.

                  TABLE 1                                                         ______________________________________                                        (1)                                                                           Water Activity                                                                Additive (alone)       Additive + gelatin                                     (A.sub.w)              (A.sub.wt)                                             25° C.                                                                              45° C.                                                                         60° C.                                                                           45° C.                                                                        60° C.                           ______________________________________                                        Lactose                                                                              38.6      31.6    32.3    57.0(57.8)                                                                           68.5(68.3)                            Powdered                                                                             11.4      22.4    26.8    57.4(59.2)                                                                           67.8(70.4)                            Sugar                                                                         Mannitol                                                                             35.4      24.1    23.1    57.8(59.2)                                                                           67.2(70.2)                            Cornstarch                                                                           41.2      61.2    73.4    67.4(60.2)                                                                           78.6(71.8)                            Crystalline                                                                          36.9      54.2    63.3    56.1(58.0)                                                                           67.4(68.5)                            cellulose                                                                     L-HPLC 15.1      30.0    38.2    45.4(51.9)                                                                           56.3(62.2)                            Gelatin                                                                              39.2      59.3    70.3    --     --                                    (alone)                                                                       PVPP    6.1      20.0    26.6    34.3(49.0)                                                                           46.9(58.9)                            Ac-Di-Sol                                                                             3.8      13.3    21.0    30.1(52.2)                                                                           41.1(62.7)                            CMC-Ca  2.2      11.4    20.0    30.9(54.8)                                                                           42.6(60.2)                            PCS    16.0      32.4    39.1    44.4(54.8)                                                                           56.8(65.1)                            ______________________________________                                         Note:                                                                         the figure in () shows the mean water activity (A.sub.w) calculated from      the measurements regarding gelatin and individual additive.              

    (2)                                                                           Water Content                                                                         Additive (alone)                                                                            Additive + gelatin                                                25° C.   45° C.                                                                         60° C.                               ______________________________________                                        Lactose   0.74            0.69    0.50                                        Powdered Sugar                                                                          0.02            0.02    0.04                                        Mannitol  0.04            0.05    0.05                                        Cornstarch                                                                              12.06           11.93   11.44                                       Crystalline                                                                             4.36            4.31    4.31                                        cellulose                                                                     L-HPLC    4.38            5.69    5.86                                        Gelatin (alone)                                                                         13.0            --      --                                          PVPP      4.61            6.83    6.81                                        Ac-Di-Sol 2.37            5.38    5.61                                        CMC-Ca    3.26            6.24    6.68                                        PCS       2.58            7.95    8.04                                        ______________________________________                                         Note:                                                                         Preserving conditions: Sealed in a vial at 25° C., 45° C. o     60° C. for 14 days (1.5 g gelatin + 1.5 g additive)                    LHPC: lowsubstituted-hydroxypropyl cellulose                                  PVPP: polyvinyl polypyrrolidone                                               AcDi-Sol (Asahi Kasei/FMC Corporation)                                        CMCCa: carboxymethyl cellulose calcium                                        PCS: partially gelatinized starch                                        

Table 1 shows that polyvinyl polypyrrolidone (PVPP), crosscarmellosesodium (Ac-Di-Sol), carboxymethyl cellulose calcium (CMC-Ca), andpartially gelatinized starch (PCS) are useful for the reduction of wateractivity inside of a capsule.

The Table 1 also shows that both the cornstarch and crystallinecellulose, which are often used in a standard formulation for capsules,function adversely to the reduction of water activity, which indicatesthat one must be careful when these additives are used in theformulation containing a drug(s) subject to influence of moisture.

Test Example 3

Stability of Aspirin in Capsules Preserved in Closed System underHeating

The test was carried out by filling a powder mixture (160 mg) of aspirin(AS) and an additive (1:1) in a hard gelatin capsule (No. 4), keepingthe capsule in a closed system set by the use of BVK14 vial whileheating at 60° C., and measuring the time-course of aspirin content. Theresults are shown in FIG. 2.

From the FIG. 2, it is clear that aspirin decomposes remarkably whenpreserved alone. The decomposition of aspirin is, however, inhibited inthe presence of partially gelatinized starch (PCS) or carboxymethylcellulose calcium (CMC), but accelerated in the presence of cornstarch(CS) or crystalline cellulose (MCC).

Test Example 4

Chemical Stability of Aspirin Capsules Containing Additives at VariousRatios

Gelatin capsules containing aspirin (AS) as a model drug at the ratio of1.5 to the gelatin were prepared in the absence or the presence of anadditive (PVPP, Ac-Di-Sol, CMC-Ca, PCS) at various combination ratios((r)=0.2, 0.5, 1.0, 1.5) to the gelatin. The capsules were thensubjected to an acceleration test (at 45° C. for 3 months) correspondingto a normal time-course test (at room temperature for 2 years), or asevere test (at 60° C. for 2 weeks), and the residual rate (%) ofaspirin and the water activity (A_(WT)) of the capsule containingaspirin were measured. The results are shown in Table 2 below.

                  TABLE 2                                                         ______________________________________                                                          Residual   Water                                                              rate (%)   activity (%)                                              Wt. ratio                                                                              45° C., 3 mon.                                                                    60° C., 2 weeks                           ______________________________________                                        AS/GEL-Cap (1.5)/1.0   84.1 (63.9)                                                                              77.2 (75.7)                                 AS + PVPP/ (1.5, 0.2)/1.0                                                                            93.3 (48.0)                                                                              83.6 (64.0)                                 GEL-Cap    (1.5, 0.5)/1.0                                                                            98.0 (42.0)                                                                              90.3 (56.2)                                            (1.5, 1.0)/1.0                                                                            99.8 (35.2)                                                                              92.8 (48.0)                                            (1.5, 1.5)/1.0                                                                           100.0 (31.2)                                                                              98.0 (44.0)                                 AS + Ac-Di-Sol/                                                                          (1.5, 0.2)/1.0                                                                            93.8 (46.4)                                                                              85.5 (60.9)                                 GEL-Cap    (1.5, 0.5)/1.0                                                                           100.0 (37.8)                                                                              90.2 (53.6)                                            (1.5, 1.0)/1.0                                                                           100.0 (30.6)                                                                              97.0 (43.2)                                            (1.5, 1.5)/1.0                                                                           100.0 (25.4)                                                                              99.9 (36.8)                                 AS + CMC-Ca/                                                                             (1.5, 0.2)/1.0                                                                            94.2 (46.5)                                                                              85.4 (62.1)                                 GEL-Cap    (1.5, 0.5)/1.0                                                                           100.0 (37.8)                                                                              92.1 (53.6)                                            (1.5, 1.0)/1.0                                                                           100.0 (32.0)                                                                              99.3 (44.5)                                            (1.5, 1.5)/1.0                                                                           100.0 (26.2)                                                                             100.0 (36.9)                                 AS + PCS/  (1.5, 0.2)/1.0                                                                            95.2 (49.1)                                                                              83.6 (66.8)                                 GEL-Cap    (1.5, 0.5)/1.0                                                                           100.0 (39.8)                                                                              92.8 (58.4)                                            (1.5, 1.0)/1.0                                                                           100.0 (39.8)                                                                              99.8 (52.2)                                            (1.5, 1.5)/1.0                                                                           100.0 (36.0)                                                                             100.0 (48.3)                                 ______________________________________                                    

The table 2 shows that, in the case of acceleration test (45° C., 3months), the aspirin content decreases to about 84% in the absence of anadditive, while the decrease in the aspirin content could be almostsuppressed by packing any one of four kinds of additives in theproportion of about 50 wt. % or more of the gelatin coating. Further,even in the case of severe test at 60° C. for 2 weeks, it is possible tosecure the aspirin residual rate of 90% or more by packing an additivein a capsule in the proportion of about 50% or more of the gelatincoating.

Test Example 5

Influence of Combination Ratio of Additive to Gelatin on Water Activity

An additive (PVPP, Ac-Di-Sol, CMC-Ca or PCS), which proved to beeffective in the reduction of water activity in Test Example 2 above,was mixed with gelatin beads at a given combination ratio (r) to obtaina mixture containing 1.5 g of gelatin beads and (1.5×(r)) g of anadditive wherein (r)=0, 0.2, 0.5, 1.0, 1.5. The resulting mixture wasthen subjected to the measurement of water activity in the same manneras described in Test Example 2 after preserving in a sealed vial for 14days under heating (25° C., 45° C. or 60° C.). The results obtainedafter preserving at 25° C., 45° C. and 60° C. are provided in FIGS. 3, 4and 5, respectively. The FIGS. 3-5 show that the additives capable ofreducing the water activity decrease the water activity of the system asa whole under any temperature condition depending on the amount used,and that the water activity of the system increases with the elevationof temperature irrespective of the kind of additive. In the figures, "a"indicates the water activity at which a crack(s) possibly happens to thenumber 4 capsule coating, which contains 4.6% PEG (polyethylene glycol)(cap & body OP. white, Japan Eranco). When the water activity decreasesbelow the value at "a", the plasticity of capsule coating woulddecrease, leading to the increase in the probability of occurrence ofcrack due to breakage during transport or preservation. As is shown inFIG. 3, the preferred combination rate of an additive to capsule coatingis 150% or less, at the storage temperature of 25° C.

Example 1

Capsules were prepared from the following components.

    ______________________________________                                        Aspirin                112.4 mg                                               CMC-Ca                  35.0 mg                                               Carplex 67 (Shionogi)   1.7 mg                                                Magnesium stearate      1.7 mg                                                                       150.8 mg                                               ______________________________________                                    

The above components were mixed and the powder mixture was filled in ahard gelatin capsule of size No. 4 (40 mg) to obtain a capsule (190.8mg).

Example 2

Capsules were prepared from the following components.

    ______________________________________                                        Aspirin                112.4 mg                                               CMC-Ca                  30.0 mg                                               Carplex 67 (Shionogi)   1.5 mg                                                Magnesium stearate      1.5 mg                                                Lactose                 9.6 mg                                                                       155.0 mg                                               ______________________________________                                    

The above components were mixed and the powder mixture was filled in ahard gelatin capsule of size No. 4 (40 mg) to obtain a capsule (190.5mg).

Example 3

Capsules were prepared from the following components.

    ______________________________________                                        Aspirin                107.0 mg                                               Ac-Di-Sol               40.0 mg                                               Carplex 67 (Shionogi)   1.0 mg                                                Magnesium stearate      2.0 mg                                                Lactose                 5.0 mg                                                                       155.0 mg                                               ______________________________________                                    

The above components were mixed and the powder mixture was filled in ahard gelatin capsule of size No. 4 (40 mg) to obtain a capsule (190.5mg).

Example 4

Capsules were prepared from the following components.

    ______________________________________                                        Aspirin                102.0 mg                                               PVPP                    48.0 mg                                               Carplex 67 (Shionogi)   1.0 mg                                                Magnesium stearate      2.0 mg                                                Lactose                 2.0 mg                                                                       155.0 mg                                               ______________________________________                                    

The above components were mixed and the powder mixture was filled in ahard gelatin capsule of size No. 4 (40 mg) to obtain a capsule (190.5mg).

INDUSTRIAL UTILITY

As is apparent from the results shown in Test Examples, the gelatincapsule of the invention keeps the water activity adequately even in aclosed system under heating. Accordingly, the present invention providesa gelatin capsule which is not only stable but also able to keep thecontent comprising a drug(s) liable to influence of moisture stably fora long term, and thereby contributing to the maintenance of the qualityof the capsules.

We claim:
 1. A gelatin capsule having adjusted water activity andpreserved in a closed system, which contains, packed therein, anadditive(s) selected from the group consisting of carboxymethylcellulose calcium, crosscarmellose sodium, and polyvinyl polypyrrolidonein the proportion of 50 to 150 wt. % of the total quantity of thegelatin of said capsule, wherein said gelatin capsule is apharmaceutically acceptable gelatin capsule.
 2. The gelatin capsule ofclaim 1 wherein the additive(s) is packed in the proportion of 50 to 120wt. % of the total quantity of the gelatin.
 3. The gelatin capsule ofclaim 2, which is packaged in a press-through package.
 4. The gelatincapsule of claim 1 wherein the additive is carboxymethyl cellulosecalcium.
 5. The gelatin capsule of claim 4, which is packaged in apress-through package.
 6. The gelatin capsule of claim 1, which ispackaged in a press-through package.
 7. A method of stabilizing apharmaceutically acceptable gelatin capsule, characterized in that anadditive(s) selected from the group consisting of carboxymethylcellulose calcium, crosscarmellose sodium, and polyvinyl polypyrrolidonein the proportion of 50 to 150 wt. % of the total quantity of thegelatin of said capsule is used as a water activity regulating agent. 8.The gelatin capsule of claim 2, wherein the additive is crosscarmellosesodium.
 9. The gelatin capsule of claim 2, wherein the additive iscarboxymethyl cellulose calcium.
 10. The gelatin capsule of claim 1,which further contains one or more pharmaceutically active ingredients.